Campylobacteriosis

Campylobacteriosis is a diarrheal disease caused by the gram-negative microaerophilic bacterium Campylobacter jejuni and less frequently by Campylobacter coli. The genus Campylobacter currently consists of 17 species, 14 of which have been isolated from humans [33]. This is an important cause of human diarrhea and has been linked to diarrhea in ferrets, mink, dogs, cats, and nonhuman primates [34].

Epizootiology and Control

Historically, Campylobacter-like organisms were thought to cause proliferative colitis in ferrets. However, it is now known that Lawsonia intracellularis causes this condition and that neither C. jejuni nor C. coli plays a role in its pathogenesis. C. jejuni is now included with Salmonella spp. and Shigella spp. as a leading cause of human diarrhea. Several reports have linked human disease to household pets, particularly dogs and cats recently obtained from animal shelters or pounds [35]. In C. jejuni prevalence studies, most positive ferrets were asymptomatic carriers. In one report, nondiarrheic feces from two commercial sources were screened, and 8 of 10 and 43 of 73 cultures taken from the two vendors were C. jejuni-positive [36]. It is not known how long ferrets naturally infected with C. jejuni shed the organism in their feces, but experimentally infected ferrets shed for up to 16 weeks after inoculation [37]. Following experimental inoculation, 10⁸–10⁹ colony-forming units (CFUs) are shed per gram of feces through day 9 post infection. A sharp shedding peak is noted at day 3, where 10¹⁰ CFUs per gram of feces are seen [38]. The high prevalence and long-term shedding of C. jejuni presents an occupational hazard to laboratory animal personnel and households with pet ferrets [39].

Foodborne and waterborne transmission appear to be the principal avenues of ferret infection, with the ingestion of contaminated meat products, such as poultry and unpasteurized milk, being particularly important. Mink kit diarrhea epizootics caused by C. jejuni and C. coli have been described and were likely associated with feeding of uncooked chicken offal [40]. Nosocomial infections are also possible, as is exposure to other pets (dogs, cats, hamsters, and birds) and to farm animals that may shed the organism [41,42]. Such transmission events are of particular concern, given the disease's subclinical nature and potential for long-term shedding and subsequent zoonotic or cross-species transmission.

Given the high prevalence of natural disease, it is not surprising that ferrets have been used to study C. jejuni-induced diarrhea and its relationship to acquired and maternal immunity [41,43,44]. In this model, self-limiting diarrhea is consistently produced. As shown in the primate model of Russell et al. [45] and the removable intestinal tie adult rabbit diarrhea (RITARD) model [46], acquired immunity provides at least partial infection resistance, manifested mainly by shortened C. jejuni colonization periods and serum antibody development. While antibodies do not prevent C. jejuni colonization, they do provide protection from diarrheal illness [37,43]. Cross-protection between C. jejuni strains has also been noted, and one study examining three different strains noted protection of 67–100% in all cases [47]. In the same report, formalin-killed C. jejuni preparations administered intragastrically provided similar protection when 4 doses were given 48 hours apart.

Clinical Signs and Pathology

Clinical diarrhea has been experimentally induced in ferrets inoculated orally with C. jejuni [44]. As in cases of Campylobacter infection in dogs and cats, ferrets can be asymptomatic carriers. Clinical diarrhea appears to occur more frequently in animals younger than 6 months of age. In addition, animals may be more susceptible to clinical infection if stressed by experimental regimens, hospitalization, concurrent disease, pregnancy, shipment, or surgery. The pathogenic mechanisms responsible for the clinical alterations and laboratory changes are poorly understood. In our experience, the typical presenting clinical signs include mucus-laden, watery, or bile-streaked diarrhea (with or without blood and leukocytes) of several days duration and partial anorexia [44,48]. Ferrets experimentally infected with C. jejuni consistently produce diarrhea within 24 hours, and 80% of infected animals have grossly apparent blood in their stool for up to 3 days [38]. In natural and experimental C. jejuni-associated colitis in mink kits, yellow-white mucoid diarrhea, often blood-tinged, has been noted [40]. Fever, rectal prolapses, and occasional leukocytosis are also seen. Adults are not affected.

In ferrets, diarrhea can persist for more than 4 weeks or may be intermittent [40]. Histopathologic changes in ferrets experimentally infected with C. jejuni consist of colonic goblet and epithelial cell loss with neutrophilic inflammation and concurrent neutropenia, particularly in the first several days following infection [37,44]. However, concurrent cryptosporidiosis, although reported to be nonpathogenic, makes lesion interpretation difficult in these cases [49]. Bacteria are noted on the colonic luminal surface, as well as within and between enterocytes. On electron microscopy, bacteria are seen attached to the epithelium with loss of associated microvilli. Intracellular bacteria are free within the cytoplasm. Following peracute disease, histopathologic changes become much less pronounced with epithelial coverage recovering by day 6 post infection [38]. Despite its reputation for colonic tropism, C. jejuni can invariably be cultured from both the small and large intestine, as well as from the livers in 78% of cases. The mechanism of hepatic translocation is not known, but presumably bacteria either travel retrograde through the biliary tree or are transported there by macrophages. Studies with the RITARD model have also demonstrated that the M cell found in the epithelial layer over intestinal Peyer's patches is a probable route for systemic spread of C. jejuni [50].

In addition to diarrheal disease, mink abortion caused by C. jejuni has been reported [51]. Experimental infections have proven that C. jejuni can also induce abortions in ferrets. In one study, four pregnant mink and seven pregnant ferrets, including five with previous exposure and specific C. jejuni antibodies, were injected intravenously with 10⁸–10¹⁰ CFUs of C. jejuni [52]. All 11 animals aborted 1–16 days after infection, with results ranging from fetal reabsorption to delivery of dead or premature living kits. In every case, uterine contents (placenta, uterine fluid, and/or kits) were C. jejuni culture-positive. In a second experiment, three pregnant mink and nine pregnant ferrets, including four with previous exposure and antibodies, were fed 10⁹–10¹¹ C. jejuni CFUs. Two of the mink aborted and kits from all three mothers were culture-positive [52]. Seven of the nine ferrets aborted, with two having C. jejuni-positive uterine contents. None of the 28 uninfected ferret control pregnancies ended in abortion. Histologically, severe placentitis was evident, and this appears a more likely cause of Campylobacter-induced abortion than direct pathogenic effects on infected fetuses. These results suggest that mink or ferret C. jejuni infection during pregnancy poses the risk of reproductive failure, even for females with previously acquired immunity.

Diagnosis

Campylobacter infection must be distinguished from other causes of diarrhea, including E. coli, Salmonella spp., and L. intracellularis. Because of its slow growth and the need for microaerobic conditions, standard methods used for culture require either filtration or selective media that incorporate various antibiotics to suppress competing fecal microflora. Cultures are incubated for 48–72 hours at 37°C and 42°C in an atmosphere containing 5–10% carbon dioxide and an equal amount of oxygen. C. jejuni colonies are round, raised, translucent, and sometimes mucoid. The organism can be identified by a series of biochemical tests readily available in diagnostic laboratories. Hippurate hydrolysis distinguishes C. jejuni from C. coli (Table 21.1). Biochemical and molecular assays should also be used to ensure that Helicobacter mustelae is not incorrectly diagnosed as C. jejuni, given their morphologic and biochemical similarities. Such confusion is possible due to the relative ease in culturing H. mustelae from ferret feces [53].

Table 21.1. Bacteriologic Properties of *Campylobacter* and *Helicobacter* spp.^a

While restriction fragment length polymorphism (RFLP) has traditionally been the gold standard for Campylobacter species discrimination, a multiplex polymerase chain reaction (PCR) assay has also been described. This technique was utilized to confirm C. jejuni identification in mink and silver fox endometritis cases and C. coli in a pig abortion case [54]. Thus, molecular analysis presents a promising new tool for confirmatory testing or in cases of ambiguous hippurate hydrolysis results. Campylobacter culture requires specialized equipment and precise technique, so the refinement of PCR-based diagnostic approaches presents an opportunity to streamline diagnosis and facilitate research. Molecular assays, particularly 16S rRNA sequencing, have resulted in the identification of several novel Campylobacter species [55].

Two widely adopted serotyping schemes used to identify C. jejuni and C. coli are the passive hemagglutination assay and the slide agglutination assay. The slide agglutination assay [56] uses heat-labile flagellar antigens (Lior serotype), whereas the passive hemagglutination assay [57] uses heat-stable antigens (Penner serotype), primarily lipopolysaccharide (LPS). Similar serotypes are recognized in both animals and humans [56,57]. Serotypes commonly isolated from humans have also been isolated from ferrets [58]. Although C. jejuni appears to be prevalent among ferrets, it is not known whether all ferret serotypes cause diarrhea in humans. Increased awareness of the zoonotic risks presented by ferrets, dogs, cats, and other domestic and laboratory animals, coupled with the utilization of reliable serotyping systems, will allow a more complete understanding of the animal host's role in human Campylobacter epidemiology [48].

Treatment

In humans, therapy for Campylobacter enteritis is primarily supportive, consisting primarily of intravenous fluid administration to replace ongoing losses. While infections are typically self-limiting without antimicrobial therapy, erythromycin has been shown to clear C. jejuni from the feces of acute enteritis patients [59] and convalescent carriers [60] within 48 hours. Thus, antibiotics shorten the typical disease course, but only when given shortly following the onset of clinical signs. Because most patients do not seek medical treatment until they have been diarrheic for several days, antibiotics are typically not utilized. However, in large-scale ferret breeding operations, antibiotic treatment might be useful to reduce colony-wide ferret morbidity and mortality during epizootics once a definitive bacteriological diagnosis is established.

In vitro sensitivity studies indicate that C. jejuni is routinely sensitive to erythromycin, aminoglycosides, tetracycline, chloramphenicol, furazolidone, and clindamycin. Erythromycin is considered the drug of choice in C. jejuni-infected humans based on susceptibility, ease of administration, and the lack of serious drug toxicity [61]. Ampicillin, metronidazole, and sulfa combinations are less therapeutically effective. Several antibiotics, including penicillin, polymixin B, cephalosporins, trimethoprim, and vancomycin are ineffective [62–64]. Many Campylobacter strains produce a β-lactamase [65], which accounts for their penicillin resistance.

A therapeutic trial was undertaken in an attempt to eliminate C. jejuni from 16 carrier ferrets. Despite their uniform in vitro sensitivity to erythromycin, oral erythromycin therapy did not eliminate C. jejuni [48]. One possible reason is that the dose used was based on that recommended for severely infected children [59]. Consequently, interspecies differences in pharmacokinetics may account for the therapeutic failure. The lack of significant pretherapy and posttherapy antibiotic mean inhibitory concentration differences indicates that resistance did not contribute to therapeutic failure [48]. Reinfection with C. jejuni could also have occurred. One day after erythromycin treatment, 6 of 16 ferrets tested negative for infection. Subsequent intestinal recolonization of five of these six ferrets may have been facilitated by environmental contamination. Unfortunately, available microbiologic techniques and standard laboratory ferret housing conditions preclude a clear-cut distinction between a chronic carrier (with lack of therapeutic response) and reinfection [48].

However, erythromycin (220 g/ton of feed) successfully controlled diarrhea and colitis associated with two Campylobacter outbreaks in weaning mink kits. Supportive treatment included warming and hydrating the animals and frequent bedding changing to keep the kits dry [40]. It is therefore recommended to treat symptomatic ferrets with C. jejuni present in diarrheic feces. Re-culture of ferrets after treatment is recommended, and precautions should be taken to minimize zoonotic transmission as well as spread to other ferrets, household pets, or other laboratory animals.

Colibacillosis and Colisepticemia

E. coli has recently gained recognition as an important ferret pathogen. These bacteria possess several virulence factors important in other species, and thus, cross-species transmission appears possible. Additionally, ferrets have been used as an experimental E. coli infection model.

Epizootiology and Control

The earliest ferret E. coli case report described gangrenous mastitis in eight ferrets [10]. While coliform mastitis may occur (see Chapter 15, “Genitourinary Diseases”), E. coli is now also considered an important cause of ferret diarrhea and septicemia. This was first reported in zoo-housed, black-footed ferrets [73]. Five adults and three kits died suddenly, either without warning or following a 24-hour period of anorexia and loose mucoid feces. E. coli was cultured from rectal swabs and necropsy tissues. Seven of the eight isolates obtained were later shown to be heat-stable toxin (STa and STb)-positive enterotoxigenic E. coli (ETEC). One isolate tested ST-negative, but was cytotoxic necrotizing factor 1 (cnf1)-positive. All isolates were nonmotile and did not react with standard O-antigen antiserum. Black-footed ferrets in this cohort were fed a mix of mink chow, raw rabbit meat, beef liver powder, lard, and blood meal. ETEC was also isolated from food that was retrieved from an affected animal's cage. When the ration batch was replaced, no new cases were noted. These animals were housed separately from one another, so foodborne transmission was considered likely, but was never definitively confirmed. E. coli-associated septicemia was diagnosed in this cohort, as ETEC was cultured from the liver, kidney, or spleen of five of these black-footed ferrets [73]. In another report, septicemia was implicated in two neonatal black-footed ferret deaths, accounting for 3% of that institution's records on neonatal mortality [74]. Septicemia could explain the acute mortality seen.

Another study examined the virulence-related properties of 40 E. coli isolates from septicemic mink [75]. Twelve O serotypes were identified, the most common of which were O8 (12 isolates) and O6 (5 isolates). Because these and 18 other avian serotypes were identified, it was speculated that they were acquired through chicken offal and uncooked egg-based feeds. PCR-based molecular testing revealed that 48% of isolates were cnf1-positive and 8% were eae-positive [75]. Diverse patterns of antibiotic resistance were noted and may be prophylactic use-related. Resistance to tetracycline (83% of isolates), sulfamethoxazole (63%), streptomycin (60%), ampicillin (38%), and kanamycin (28%) were most commonly encountered. Multiple resistances were common, as 50% of isolates were resistant to four or more antibiotics. Conjugation experiments demonstrated R plasmid transmission in at least 27% of isolates. All isolates were susceptible to amikacin, ciprofloxacin, ceftiofur, ceftriaxone, cefoxitin, amoxicillin with clavulanic acid, and imipenem [75].

Other studies have also examined antibiotic resistance in farmed mink. One study compared resistance patterns in isolates from apparently healthy and diarrheic animals from different farms [76]. Tetracycline (22%), amoxicillin (23%), sulfamethoxazole (30%), spectinomycin (22%), and trimethoprim (10%) resistance was encountered, though farm-to-farm variability was high. All isolates were colistin, gentamicin, neomycin, and enrofloxacin susceptible. Hemolytic isolates, of which approximately equal numbers were obtained from diarrheic and healthy mink, were approximately twice as likely to display resistance. Another study similarly examined 1093 mink E. coli isolates cultured from both intestinal and extraintestinal (lung, liver, spleen, or urogenital) samples [77]. Fecal and intestinal samples most commonly displayed resistance to ampicillin (39%), streptomycin (26%), tetracycline (24%), sulfamethoxazole (24%), spectinomycin (11%), and trimethoprim (10%). These were also the most commonly encountered resistance phenotypes in extraintestinal E. coli isolates, though some site-specific variation was encountered. Very low resistance frequencies (less than 5%) were noted to fluoroquinolones, gentamicin, florfenicol, amoxicillin with clavulanic acid, ceftiofur, chloramphenicol, colistin, nalidixic acid, and apramycin.

cnf1-Positive E. coli have been identified in septicemic black-footed ferrets and mink [73,75]. This protein toxin is associated with human necrotoxigenic E. coli (NTEC) implicated in extraintestinal infections, including meningitis and approximately 80% of uncomplicated human urinary tract infections [78]. Ferret-origin E. coli isolates from rectal, urine, vaginal, milk, brain, and blood cultures produce functional CNF1, directly implicating this toxin in disease [79]. While cnf1 warrants further study in this context, its association with ferret and mink intestinal and extraintestinal disease merits its inclusion in virulence factor-based molecular screens.

While never definitively reported, ferret E. coli isolates have zoonotic potential. Ferret isolates share numerous virulence factors with human- and animal-origin pathogenic E. coli, such as eae, cnf1, and enterotoxins. Ferrets have also been experimentally infected with O157:H7 and other shiga toxin-producing E. coli (STEC) isolates. Infected ferrets maintained a local gastrointestinal infection and in 23% of cases developed evidence of renal disease, frequently including glomerular capillary fibrin deposition and hematuria. Glomerular damage and hematuria without bacteremia are consistent with the features of human hemolytic uremic syndrome [80]. In addition to this infection model, experimental pig and rabbit infections with bovine- and human-origin isolates further support that E. coli transmission is not host-dependent [81]. Evidence also suggests that isolates from animals and humans share a high degree of clonality [82], reinforcing the importance of animals as pathogenic E. coli reservoirs [83]. Human handlers should approach diarrheic ferrets with caution and utilize personal protective equipment to minimize transmission risks. Children should not be permitted contact with diarrheic animals due to their E. coli-induced hemolytic uremic syndrome susceptibility.

Clinical Signs and Pathology

Ferrets infected with pathogenic E. coli will most likely present with diarrhea. Its duration, severity, consistency, and the presence/degree of hematochezia are strain-dependent. Diarrhea may assume a rapid course or could be several weeks in duration. Fever, dehydration, anorexia, and abdominal pain may also be present. Ferrets with colisepticemia present in shock or are found dead following 12–24 hours of anorexia or lose mucoid stool.

Upon necropsy, redness of the gastrointestinal mucosa may be noted. Also, intestinal contents may be bloody, mucoid, or watery in a strain-dependent manner. Histopathologically, ferrets display enterocolitis with large numbers of rod-shaped bacteria associated with intestinal villi [73]. Inflammation is typically neutrophilic and may be associated with fibrinonecrotic debris adhered to the intestinal lumen.

Diagnosis

Pathogenic E. coli diagnosis is based on aerobic culture of either feces or intestinal tissues. At 37°C, E. coli grows readily on blood agar and on MacConkey agar, where it is lactose-fermenting. Because it is a normal ferret intestinal flora component, subsequent PCR-based testing should be used to confirm the presence of virulence determinants. Due to the broad range of potentially pathogenic ferret E. coli isolates that have been obtained, PCR tests for intimin, shiga-like toxins 1 and 2, heat-stable and heat-labile enterotoxins, and cytotoxic necrotizing factors 1 and 2 should be performed. Toxin liberation can be verified by adding liquid E. coli culture supernatant to cultured cells. Mannose-independent bacterial HEp2 and HeLa cell adherence has also been used as an adjunct E. coli virulence assay for human clinical isolates [84]. Because a variety of E. coli serogroups infect ferrets, serologic typing appears inferior to molecular diagnostics in determining E. coli isolate virulence. However, serotyping may be useful as an adjunct to other methods, such as pulsed-field gel electrophoresis and repetitive sequence-based PCR, in determining isolate relatedness during epizootics. E. coli infection must be distinguished from other causes of enterocolitis in ferrets, including Campylobacter, Salmonella, and L. intracellularis.

Treatment

Because of the rapid-onset septicemia seen in many ferrets, empirical treatment should be instituted when colibacillosis is suspected. Antibiotics should be given immediately and adjusted based on culture sensitivity. Fluid losses and electrolyte abnormalities from diarrhea should be corrected through early isotonic crystalloid therapy.

Helicobacter mustelae

Historically, the normal stomach was considered bacteriologically inert because of the bactericidal effect of low gastric pH. During the past 25 years, studies in humans have shown that a newly recognized bacteria, Helicobacter pylori, causes gastritis, is causally associated with peptic ulcer disease, and is linked epidemiologically to gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma [89].

Epizootiology and Control

In 1985, a gastric Helicobacter-like organism was isolated from the margins of a ferret's duodenal ulcer [90] and was named H. mustelae [91]. Subsequently, in the United States, gastritis and peptic ulcers have been routinely reported in H. mustelae-colonized ferrets [92,93]. Virtually, every ferret with chronic gastritis is H. mustelae-infected, whereas uninfected specific pathogen-free (SPF) ferrets do not have gastritis, gastric ulcers, or detectable immunoglobulin G (IgG) antibodies [93–95]. Koch's postulates have been fulfilled by oral H. mustelae inoculation of naive ferrets. The resulting infection induced a chronic, persistent gastritis similar to natural infection [96]. H. mustelae has been isolated from ferret stomachs in England, Canada, and Australia but not from ferrets in New Zealand [97,98]. The mild gastritis noted in England may reflect sparse H. mustelae colonization in younger animals or reduced pathogenicity compared with American strains [98].

H. mustelae colonizes nearly 100% of ferrets shortly after weaning. Weanling and adult ferret feces have been screened to determine whether fecal transmission could explain this high prevalence [92,99]. H. mustelae was isolated from 8 of 74, 9-week-old ferrets, and 3 of 8, 8-month-old ferrets. These results were based on biochemical and phenotypic criteria as well as DNA probes and 16S rRNA sequencing [99]. H. mustelae was not recovered from the feces of 20-week-old ferrets that were positive at weaning or from the feces of l-year-old ferrets. However, given that H. mustelae persistently infects the ferret stomach, it is likely persistently shed. Further studies are needed to confirm this hypothesis.

During experimental ferret H. mustelae infection, transient hypochlorhydria was observed approximately 4 weeks after infection [96]. This period coincided with heavy H. mustelae colonization of the fundus. In ferrets experimentally infected for longer than 8 weeks, the organism (as in most naturally infected ferrets) colonized the antrum in greater numbers [96]. To test whether hypochlorhydria enhanced fecal H. mustelae recovery, oral omeprazole was administered to adult ferrets to induce gastric hypochlorhydria [53,96]. H. mustelae was isolated from sequential fecal samples in 23 of 55 ferrets (41.8%) during omeprazole therapy [53]. However, when the same group was not receiving omeprazole treatment, only 6 of 62 ferrets (9.3%) were H. mustelae-positive. All gastric biopsy samples were H. mustelae-positive, and in four of five ferrets their restriction enzyme patterns were identical to fecal H. mustelae strains. These findings favor the hypothesis that hypochlorhydria promotes fecal-oral spread [53,96].

Clinical Signs and Pathology

In our laboratory, H. mustelae-infected ferrets are usually asymptomatic. Those with endoscopically visible gastric or duodenal ulcers can be recognized clinically by vomiting, melena, chronic weight loss, and lowered hematocrit. Acute gastric bleeding episodes are also occasionally noted [100] (Fig. 21.3 and Fig. 21.4). Clinical signs in ferrets with H. mustelae-associated gastric adenocarcinoma have included vomiting, anorexia, and weight loss—all signs easily confused with gastric foreign body [101].

c21-fig-0003 — Fig. 21.3. Female young adult lumen of stomach containing blood from a gastric ulcer.

c21-fig-0004 — Fig. 21.4. Female young adult rectal melana resulting from gastric ulcer.

In addition, like H. pylori-infected humans, H. mustelae-infected ferrets have hypergastrinemia, another feature that may be directly related to ulcerogenesis [102]. The plasma gastrin responses in H. mustelae-infected and noninfected ferrets are consistent with those in H. pylori-infected and H. pylori-eradicated humans, respectively (Table 21.2) [103–108]. Specifically, H. mustelae-infected ferrets have a significantly greater and more sustained increase in meal-stimulated plasma gastrin [102].

Table 21.2. Plasma Gastrin Concentrations in Ferrets of the Study (Mean ± SEM)

Gastric Helicobacter-induced hypergastrinemia may be related to peptic ulcer disease pathogenesis in ferrets and other animals. The combination of parietal cell trophic effects and increased gastric acid secretion may lead to upper gastrointestinal mucosal damage and ulcer formation. Abnormal gastrin hypersecretion may be a key element of Helicobacter-associated peptic ulcer disease pathogenesis. Current proposed mechanisms of human H. pylori-induced hypergastrinemia include G cell stimulation by amines or H. pylori-produced peptides, G cell stimulation by inflammatory cell cytokines, or selective somatostatin cell destruction or inhibition leading to the loss of somatostatin-mediated gastrin inhibition [108,109]. Thus, hypergastrinemia is attributable to either the bacterium itself or antral inflammation. H. pylori eradication leads to hypergastrinemia resolution. Because antibiotic therapy has been used successfully to eradicate H. mustelae from ferrets [110], studies in H. mustelae-infected and H. mustelae-eradicated ferrets can be undertaken to further investigate the mechanisms inducing hypergastrinemia. Future experiments are needed to determine the time interval for peak meal-stimulated gastrin secretion in ferrets, as are studies to determine whether H mustelae eradication results in decreased plasma gastrin concentration similar to human H. pylori eradication [103–108,111–114].

Gastric histopathologic changes closely coincide topographically with H. mustelae [94]. Superficial gastritis of the stomach body is associated with localization on the mucosal surface but not in the pits. In the distal antrum, inflammation occupies the full mucosal thickness, consistent with the diffuse antral gastritis described in humans. In this location, H. mustelae is seen at the surface, in the pits, and on the superficial portion of the glands. In addition, focal glandular atrophy (a precancerous lesion) and regeneration occur in the proximal antral and transitional mucosa. Also, deep H. mustelae colonization is focally observed in affected antral glands (Fig. 21.5). The H. mustelae-associated gastritis in the distal antrum and oxyntic mucosa also closely resembles human diffuse antral gastritis, which (as in the ferret) is usually accompanied by superficial gastritis of the stomach body. These clinicopathologic findings often underlie the duodenal ulcer syndrome [115,116]. Interestingly, the ferret is the only domesticated animal where naturally occurring Helicobacter-associated ulcer disease has been described (Fig. 21.6 and Fig. 21.7). The proximal antral and the transitional zone gastritis represent early-stage human multifocal atrophic gastritis, the entity underlying the gastric ulcer and gastric carcinoma syndromes [115,116]. The gastric disease severity increases as animals age (Table 21.3) [93].

c21-fig-0005 — Fig. 21.5. *H. mustelae* in mucosal crypt of stomach. Warthin–Starry stain (see arrows).

c21-fig-0006 — Fig. 21.6. Histopathologic illustration of gastric ulcer (arrow) and chronic inflammation, loss of fundic glands in a ferret with *H. mustelae*. H&E Stain.

c21-fig-0007 — Fig. 21.7. Diffuse gastritis with erosive lesions and exfoliative exudates in the lumen in the fundus of a ferret infected with *H. mustalae.*

Table 21.3. Severity of *H. mustelae-*Associated Gastritis Related to Ferret Age

Ultrastructural examination of ferret antral gastric tissue show that H. mustelae localizes within the gastric pits with little evidence of bacteria on the external surface or in the overlying mucus layer [116] (Fig. 21.8). H. mustelae are instead very closely associated with the epithelial cells. Organisms are present alongside microvilli perpendicular to epithelial cell surfaces and in some instances are seen penetrating these cells. Extensive microvilli loss and adhesion pedestals are visible. Occasionally, H. mustelae organisms are localized intraepithelially within membrane-bound inclusions, indicating their endocytic uptake. A dense fibrous-like matrix or glycocalyx exists between epithelial cells and H. mustelae when the two surfaces are very close together. H. mustelae is also present in intercellular junctions, but large bacterial numbers are not noted, unlike in human H. pylori infection [117,118]. Thus, close H. mustelae attachment may play a role in ferret peptic ulcer disease development as in H. pylori infection.

c21-fig-0008 — Fig. 21.8. Pure culture of *H. mustelae* showing rod-shaped morphology and long polar and lateral flagella. (A) Transmission electron microscopy. (B) Phase contrast microscopy. (C) Bacteria penetrating into epithelial cells. Scale bars = 0.2 μm (A) 0.5 μm (C), 0.1. (Modified from Fox JG, Lee A. (1997) The role of *Helicobacter* species in newly recognized gastrointestinal tract diseases of animals. Lab. Anim. Sci. 47: 222.)

In vitro adhesion studies have shown that H. mustelae, like H. pylori, has specific ligand interaction with host lipid receptors [119,120]. Likewise, studies of H. mustelae and H. pylori cell surface properties indicate that they possess both hydrophobicity and hydrophilicity in an assay-dependent manner [121]. Studies imply, however, that the H. mustelae cell surface is relatively hydrophilic with distinct hydrophobic domains [121]. The ferret stomach is more hydrophobic than the large or small intestine. Interestingly, H. mustelae-infected inflamed gastric mucosa has a reduced mucosal hydrophobicity, which is consistent with human H. pylori infection [122]. Reduction of gastric epithelial mucus layer hydrophobicity may be responsible for this phenomenon [122]. These features may contribute to the pathogenesis of H. mustelae.

An isogenic urease-negative H. mustelae mutant was constructed to investigate urease's role in gastric mucosa colonization [123]. All four ferrets given the mutant strain remained uninfected throughout the study. Wild-type H. mustelae-infected ferrets exhibited diffuse mononuclear inflammation in the subglandular region and lamina propria of the gastric mucosa, whereas uninfected ferrets showed no or minimal inflammation. Thus, the inability of urease-negative H. mustelae to colonize the ferret gastric mucosa confirmed germ-free piglet studies in which isogenic urease-negative H. pylori mutants failed to colonize the stomach [124]. These studies proved urease's importance in gastric Helicobacter pathogenesis.

H. mustelae, like H. pylori, possesses two flagellin molecules, FlaA and FlaB [125,126]. To determine whether one or both proteins is necessary for pathogenesis, isogenic H. mustelae mutant strains were constructed where either or both genes were disrupted. Ferrets were given the FlaA (moderately motile), FlaB (weakly motile), or FlaA/B (nonmotile) mutant strain, the wild-type parent strain, or sterile broth [127]. Three-month infection with the H. mustelae wild-type parent strains and the FlaB mutant strain produced a mild lymphocytic and lymphofollicular gastritis, whereas infection with the FlaA mutant strain produced only minimal to mild mononuclear cell gastritis. The double mutant strain did not colonize, whereas the FlaA and FlaB single mutant strains initially colonized the ferret stomach at low levels, established a persistent infection, and generated increased H. mustelae numbers over time. Also, gastritis severity correlated with gastric bacterial numbers. Therefore, flagellar-induced motility, like urease, is an important H. mustelae virulence factor [127]. The publication of the H. mustele genome will further enhance study of its virulence properties [128].

Naturally Occurring Gastric Cancer

Because H. pylori-associated gastric adenocarcinoma remains an important cause of human morbidity and mortality, it is important to consider the gastric cancer susceptibility of Helicobacter-infected animals [53,129–131]. We documented argyrophilic bacteria, consistent with H. mustelae in location and morphology, within the pyloric mucosa of two male ferrets with pyloric adenocarcinoma [101]. In another pyloric adenocarcinoma case, argyrophilic bacteria with H. mustelae-like morphology were also seen within pyloric pits, and the neoplasms manifested as multiple foci of tubules lined by mucous epithelium that invaded into the deep submucosa, resulting in a significant local scirrhous response [132]. The discrete invasive characteristics suggested that the neoplasms represented early cellular infiltration beyond carcinoma in situ. The neoplastic growth patterns resembled the description of three naturally occurring pyloric adenocarcinomas previously reported [133,134]. This pattern was also seen in N-methyl-N-nitro-N′-nitrosoguanidine-induced gastric adenocarcinomas in H. mustelae-infected ferrets [53]. The young adult ages in this (2 and 3.5 years) and other (3 to 4 years) cases suggest early disease progression (Fig. 21.9) [133,134].

c21-fig-0009 — Fig. 21.9. Ferret male, 21-months- thickened stomach wall; diagnosed with gastric adenocarcinoma.

More confluent, highly anaplastic, and transmurally invasive adenocarcinomas, consistent with protracted tumor progression, were also reported in an older ferret [132]. Osseous metaplasia was noted in the tumors, providing a useful marker during radiographic examinations [53,133,134] (Fig. 21.10). Unlike the previous reports that cited poor prognosis associated with ferret gastric adenocarcinoma, both ferrets in the recent report responded well to surgical intervention and remained asymptomatic postoperatively for 1 year and 6 months, respectively [132]. Thus, the presence of naturally occurring H. mustelae-associated gastric adenocarcinoma supports the epidemiologic association between H. pylori infection and gastric cancer risk in humans [135–139]. Additionally, H. pylori-associated MALT lymphoma has been recently described in humans, and we have recently documented several H. mustelae-infected ferrets with the same syndrome [140] (see Chapter 9).

c21-fig-0010 — Fig. 21.10. Calcification of extraintestinal tissue (infected with *Lawsonia* sp.) that has translocated to omentum, mesenteric lymph nodes, and capsule of liver. Lateral (A) and dosoventral views (B).

We also have noted possible Helicobacter-associated cholangiohepatitis and neoplasia in a group of co-housed pet ferrets. Eight of 34 (24%) of ferrets, all 5- to 8-years old, exhibited chronic cholangiohepatitis and bile duct hyperplasia, as well as variable oval cell hyperplasia, cystadenoma, and hepatocellular or cholangiocellular degenerative change. Cholangiocellular carcinoma was identified in two of eight ferrets. Spiral-shaped argyrophilic organisms, sharing sequence similarity with H. cholecystus, were identified in three ferrets, including both animals with carcinoma. While co-housing supports an infectious etiology, the precise role of Helicobacter spp. in ferret hepatobilliary disease remains poorly defined [141] (see Chapter 16, “Gastrointestinal Diseases”).

Diagnosis

Ferret H. mustelae isolates have biochemical features similar but not identical to H. pylori, particularly in regard to abundant urease production (Table 21.1). For culture, gastric biopsy or necropsy tissues are transported in sterile phosphate-buffered saline and processed within 1 hour of collection. Gastric samples are minced with sterile scalpel blades and inoculated onto blood agar plates supplemented with trimethoprim, vancomycin, and polymixin B (Remel, Lenexa, KS). The plates are incubated at 37°C or 42°C in a microaerobic atmosphere (80% N₂ 10% H₂ and 10% CO₂) for 3–7 days. Bacteria are identified as H. mustelae on the basis of Gram stain morphology, urease, catalase, and oxidase production, cephalothin resistance, and nalidixic acid sensitivity (Table 21.1).

A provisional gastric Helicobacter diagnosis takes advantage of their unique ability to produce large quantities of urease. Gastric biopsy specimens containing bacteria can be placed in urea broth containing a pH indicator (phenol red) and a preservative (sodium azide) to help prevent false-positive reactions due to urease-positive bacterial contaminants. The broth assay is then visually monitored over 16 hours. A deep pink color change, caused by the enzymatic breakdown of urea to ammonia, indicates a positive reaction. Also, a semiquantitative assessment of H. mustelae numbers can be inferred by color change speed. A test is available commercially, but a microtiter tray with a measured amount of urea test solution delivered to each well can be effectively and economically used. The urea breath test, which measures expired radiolabeled carbon dioxide consumed in a test meal, is used in humans but has only been perfected under experimental conditions in ferrets [142].

Although infected animals and humans mount a significant systemic IgG response to gastric Helicobacter, the immunoglobulins are not protective. Nonetheless, a serologic assay is being used to diagnose human H. pylori and ferret H. mustelae infections. This enzyme-linked immunosorbent assay provides a reliable noninvasive diagnostic test for H. mustelae infection [94]. An H. pylori detection assay performed on stool is routinely used to diagnose human disease, and a comparable ferret test might prove useful in H. mustelae diagnosis.

Treatment

Triple therapy consisting of oral amoxicillin (30 mg/kg), metronidazole (20 mg/kg), and bismuth subsalicylate (17.5 mg/kg, Pepto-Bismol original formula, Proctor & Gamble, Cincinnati, OH) 3 times a day for 3–4 weeks has successfully eradicated H. mustelae from ferrets [110]. In addition, a treatment regimen used to eradicate human H. pylori has been successfully used to eradicate ferret H. mustelae [143]. Ferrets received 24-mg/kg ranitidine bismuth and 25-mg/kg clarithromycin orally 3 times daily for 2 weeks. H. mustelae cultured gastric biopsy specimens obtained at 16, 32, and 43 weeks after treatment termination indicated that long-term eradication was achieved in six of six ferrets. With eradication, gastritis diminished and H. mustelae-specific IgG antibody decreased. These results are consistent with findings in humans following H. pylori eradication.

In ferrets, daily oral omeprazole at 0.7 mg/kg effectively induces hypochlorhydria [99] and may be used in conjunction with antibiotics to treat H. mustelae-associated duodenal or gastric ulcers. Oral cimetidine (10 mg/kg 3 times a day) can also be used to suppress acid secretion. Acute bleeding ulcers must be treated as emergencies, and fluid and blood transfusions are essential.

Mycobacteriosis

The ferret appears to be highly susceptible to certain Mycobacterium species of avian, bovine, and human origin. Disease may be subclinical or produce nonspecific clinical signs and therefore escape detection, thus potentiating disease spread among animals and zoonotic transmission to pet owners or laboratory personnel.

Epizootiology and Control

Only scattered reports of ferret mycobacterial infection appear in the literature, almost exclusively in English and European research ferrets from 1929 to 1953 [155,156]. One investigator reported that among thousands of necropsies performed on dealer-obtained ferrets, 60% were infected with Mycobacterium—most commonly avian strains and, less frequently, bovine strains [157,158]. However, a wildlife survey utilizing pooled lymph nodes from more than 22,000 mustelid spp. identified 476 Mycobacterium isolates [159], 56% and 44% of which were Mycobacterium bovis and Mycobacterium avium complex, respectively. Forty-eight M. bovis isolates were subjected to restriction enzyme analysis, which identified 23 unique types, most of which are associated with both domestic animals and wildlife. The disease continues to be recognized in New Zealand ferret farms [160]. Atypical mycobacterium infection due to M. avium has been recently diagnosed in an American pet ferret [161].

The ferret can be naturally or experimentally infected with bovine, avian, and human Mycobacterium species. Historically, ferret infection was recorded when feeding unpasteurized milk, raw poultry, and meat (including meat by-products) was routinely performed. Feeding of infected carcasses or milk likely contributed to disease incidence during this era. Chicken offal used in preparing mink ration, which is also fed to ferrets, can be a possible infection source [162]. Efforts to eliminate tuberculosis in commercially reared livestock and chickens have effectively reduced this disease's incidence. In addition, the general use of commercially prepared cat or ferret diets as sole ferret food sources has appreciably reduced the possibility of disease introduction. Mathematical models suggest that transmission within wild ferret populations is also primarily through food contamination [163]. This was hypothesized because age-prevalence curves indicated a sharp increase in infection following weaning that remained throughout life. Higher male disease prevalence was accounted for by factors such as home range size, susceptibility, and dietary composition. Additionally, wild birds, which can shed avian mycobacteria in their feces, may contaminate feed supplies and outdoor ferret housing areas. M. bovis has also been transmitted from experimentally infected ferrets to 75% of co-housed, noninfected ferrets [164]. It was suggested that factors such as playing, fighting, cannibalism, mating, and fecal exposure may have been involved.

Clinical Signs and Pathology

Clinical signs exhibited by infected ferrets are poorly documented, highly variable, and nonspecific. Systemic infection caused by bovine strains results in generalized weight loss, appetite loss, lethargy, and death. In one well-documented tuberculosis case caused by a bovine-origin strain, the ferret had hind limb paralysis that began with difficulty walking and progressed to hind limb splaying. Bacteria isolated from this animal were inoculated intramuscularly into another ferret, which remained normal until 6 months later, when it developed paralysis of the adductor thigh muscles. Eventually, all muscles of the limbs were affected [157]. Splenomegaly, hepatomegaly, and intestinal nodules can also be palpated in disseminated disease.

Disseminated disease is more likely with M. bovis, whereas the human and avian tubercle strains usually produce only local, indolent tubercular lesions. In one report, nine experimentally M. bovis-infected ferrets had macrophage infiltration most frequently in the liver [164]. Infiltration was also variably noted in the mesenteric, retropharyngeal, bronchial, and mediastinal lymph nodes. Acid-fast bacilli were noted in the thoracic lymph nodes in five of nine ferrets, but were not identified in the liver or mesenteric lymph nodes.

In vitro phytohemagglutinin (PHA) responses of normal versus M. bovis-treated ferret peripheral leukocytes demonstrate that M. bovis PHA suppression correlates with M. bovis peripheral leukocyte cytotoxicity. M. bovis concentrations 10⁶/mL and below enhance the PHA response, but more than 10⁶ organisms/mL suppresses it [165]. Thorns and Morris [165] speculated that the cytotoxic activity of high M. bovis concentrations and associated in vitro PHA-stimulated leukocyte suppression may play a role in disease pathogenesis by depressing specific and nonspecific cell-mediated immunity. This explains the lack of cellular tissue reactions seen in naturally occurring M. bovis ferret disease.

In another case, a pet ferret presented with intermittent anorexia, diarrhea, and vomiting of 6 weeks' duration [161]. Supportive care was given for another 3 weeks without resolution of signs. Radiography with barium indicated delayed gastric emptying. A midline exploratory celiotomy was performed, a 1 cm constricted band was located in the proximal jejunum, and the intestine was dilated proximal to the constriction. A resection and anastomosis was performed, and the resected tissue revealed granulomatous jejunal inflammation. Diffuse macrophage infiltration with intracellular acid-fast organisms was also observed in a mesenteric lymph node biopsied during surgery [161]. The ferret responded to the surgery and did well for the next 8 months, when vomiting and weight loss recurred. Abdominal surgery revealed a 1-cm diameter pyloric mass that projected into the gastric lumen. This mass was resected, but despite surgical intervention and treatment, the animal's condition deteriorated and it died 2 weeks later. Necropsy revealed a thickened pylorus. Multiple tissues were submitted for microscopic analysis, and liver and spleen sections were cultured. Histologically, sheets of macrophages were seen in the lamina propria and submucosa. Severe granulomatous inflammation was also noted in the jejunum, stomach, and mesenteric lymph nodes. Additionally, small granulomas were noted in the liver and spleen. Intracellular acid-fast organisms were present in the jejunum and elsewhere, and M. avium was subsequently cultured from the liver and spleen.

M. avium was also reported in a 6-year-old pet ferret with chronic weight loss accompanied by leukocytosis and anemia [166]. Radiography revealed hepatomegaly and a left cranial abdominal mass. Because metastatic neoplasia was suspected, euthanasia was elected. Upon necropsy, mesenteric lymph node enlargement, multifocal tan hepatic nodules, and a thickened stomach were evident. Both neoplastic cells and granulomatous inflammation were evident in these locations, and acid-fast bacilli were present within macrophages. Non-paratuberculosis M. avium was identified by PCR, and it was hypothesized that large cell lymphoma-mediated immunosuppression facilitated disseminated mycobacterial infection.

Granulomatous enteritis with acid-fast organisms present in hepatic, colonic, and mesenteric lymph node lesions, as well as fecal smears, has also been reported in two laboratory ferret groups with diarrhea of several months' duration. Unfortunately, the bacteria were not cultured or identified [167]. Pulmonary M. avium has also been reported in ferrets maintained in a French zoological garden [168].

Mycobacterium celatum, which infects immunosuppressed humans, has been identified in three ferrets [169–171]. In these cases, 3- to 5-year-old ferrets presented with 2- to 6-month histories of weight loss with variable coughing, depression, muscle atrophy, vomiting, and mild diarrhea. Multifocal pulmonary nodules were evident radiographically, and euthanasia was elected in all cases. On necropsy, firm 2- to 10-mm, pale gray to light brown nodules were randomly distributed throughout the lung parenchyma. Lymphadenopathy and splenomegaly were variably evident, as were smaller 1- to 2-mm pale hepatic foci. In two cases, granulomatous lesions were evident microscopically, and acid-fast bacteria were located within lesions and inside macrophages. In the third case, antemortem ultrasound-guided fine needle aspirates identified the bacterium within macrophages. While no mycobacteria were cytologically evident, chronic systemic antimicrobial therapy was unsuccessful, and its discontinuation precipitated decline and death. In all three cases, culture followed by 16S rRNA sequencing confirmed the etiologic agent.

Mycobacterium abscessus has been associated with pneumonia in two co-housed ferrets [172]. Again, weight loss and coughing were the primary symptoms; bronchoalveolar lavage (BAL) identified a primarily neutrophilic inflammatory response, and acid-fast bacilli were noted within macrophages. BAL fluid culture yielded bacterial colonies within 5 days, consistent with this organism's rapid growth. Another report describes Mycobacterium genavense infection associated with disseminated lymphatic infection and conjunctivitis in a ferret [173]. This is another saphrophytic Mycobacterium species associated with human AIDS patients. Lymph node cytology and conjunctival biopsy, followed by staining and 16S rRNA sequencing, confirmed infection.

Diagnosis

Nodular lesions, if calcified, can be demonstrated radiographically. Laparotomy, with biopsy of involved abdominal lymph nodes and other organs and bacterial isolation, will establish a definitive diagnosis. M. avium was isolated from ferret tissue by macerating infected tissue in a cetylpyridinium chloride solution (7 g/L of distilled H₂O, Sigma Chemical, St. Louis, MO) for 3 hours. Following centrifugation at 300× g for 15 minutes, sediment was inoculated onto Herrold's egg yolk media slants and incubated for 3 weeks at 35° and 42°C [161]. Additionally, PCR-based M. tuberculosis diagnosis is being used with increasing frequency in humans and has also been utilized to confirm and speciate ferret infections [166]. Immunohistochemical reagents are also available, though species specificity may not be reliable [169].

Experimentally, ferrets inoculated with Freund's complete adjuvant (FCA, containing killed M. tuberculosis) react to an intradermal 10⁴ U (200 μg) tuberculin injection (see Chapter 7) [174]. In other studies, ferrets inoculated with both FCA and 10⁴ and 10⁵ U of tuberculin had skin reactions 14 days later [175]. Skin tests carried out 4 weeks after this treatment were negative. However, in ferrets experimentally infected with M. bovis, a minimal tuberculin response to purified protein derivative (10 μg/mL) was observed only 36 hours after inoculation, and no response was observed at 7 and 15 days after inoculation [176]. The tuberculin skin test was used to eliminate natural tuberculosis cases in a ferret breeding colony [177]. Unfortunately, the tuberculin type and dosage were not detailed. Depending on the infecting Mycobacterium strain, reaction to a purified protein derivative tuberculin test may be minimal. For example, Pulling [178] found that mink from a tuberculous colony tested by intradermal bovine tuberculin injection did not show a delayed hypersensitivity reaction.

Treatment

Because of the zoonotic risk associated with tuberculosis, M. tuberculosis- or M. bovis-infected ferrets should be euthanized. Although M. avium is not a disease reportable to public health officials, its presence may present a zoonotic risk, particularly in immunocompromised humans. If other ferrets have been exposed, they should be tuberculin-tested (which may not be helpful), or other diagnostic tests should be performed to ascertain their disease status. Personnel at risk should also be screened with appropriate tuberculin tests.

Zoonosis

Recurrent M. bovis infection following a ferret bite has been recorded [179]. In 1991, a 63-year-old man presented with a 3-week history of right palm swelling that became red, tender, and painful. Pyrazinamide-resistant M. bovis was isolated. Subsequent treatment with ethambutol for 2 months, together with rifampin and isoniazid for 7 months, led to an uneventful recovery. The patient had been bitten by a ferret 22 years earlier. The chronic swelling situated above the carpus badly impaired finger mobility. Histologically, the patient had tuberculous synovitis, and M. bovis was isolated. Previous therapy with streptomycin sulfate with supplemental para-aminosalicylic acid and isoniazid, although apparently clinically successful, had not completely eradicated the bacterium, and subsequent infection reactivation occurred [179]. Molecular evidence also supports M. bovis human–ferret transmission [180]. In one study, 43% and 26% of human- and ferret-origin isolates, respectively, shared restriction enzyme analysis (REA) patterns with isolates from the other species. However, population modeling suggests that wild ferrets residing in New Zealand do not exist at sufficiently high density to act as sole M. bovis maintenance hosts, emphasizing the importance of other wildlife species in this dynamic [181].

Proliferative Bowel Disease

Proliferative bowel disease was first reported in research ferrets in 1983 [41] and in a pet ferret in 1986 [187]. It was initially classified as a Campylobacter-like organism similar to those noted in hamsters, rabbits, and pigs. The organism was formally named L. intracellularis in 1995 and is now recognized as a common clinical entity in weanling ferrets.

Epizootiology and Control

Proliferative bowel disease was originally described in a research ferret colony, where 31 of 156 (20%) ferrets developed protracted diarrhea over a 4-month period [41]. Ten of these were examined by necropsy and histology and were found to have proliferative bowel disease. Although C. jejuni was isolated from 6 of 10 ferrets, the causal organism was an intracellular Campylobacter-like organism closely related to Desulfovibrio spp. [41]. L. intracellularis, as it is now classified, is appreciated as an important cause of intestinal disease in many species, including ferrets, pigs, hamsters, horses, rabbits, primates, and deer. Isolates from these species appear closely related, and the ability to reproduce the pig disease syndrome in hamsters and mice suggests a low degree of host restriction [188,189]. Exposure to other species known to harbor L. intracellularis should be considered a potential source of infection. It is also possible that interaction with other gastrointestinal bacteria modulates disease, as L. intracellularis-inoculated, restricted flora piglets fail to become colonized or develop disease [190]. Similar piglets receiving L. intracellularis and other enteric bacteria reproduce typical proliferative enteropathy [191]. Additionally, simultaneous infection with L. intracellularis and enteropathogenic E. coli (EPEC) has been characterized in rabbits, and synergism associated with high mortality was suggested [192]. Little is known regarding precise transmission mechanisms, though fecal-oral spread is suspected. It is thought that environmental sanitation and reduced exposure to adult ferret feces, coupled with maintenance of a high nutritional plane in young ferrets, may reduce disease severity.

Clinical Signs and Pathology

In the original disease description, 10 animals ranging in age from 4 to 6 months presented with diarrhea, weight loss, and rectal prolapse (Table 21.4) (Fig. 21.11. Fecal material was usually blood-tinged, often discolored green, and contained mucous. Intermittent diarrhea persisted for more than 6 weeks. Seven of the 10 animals exhibited more than a 100-g weight loss during the first 2–4 weeks of illness. Affected males lost 12–54% of their body weight, and affected females lost 30–54%. Several ferrets exhibited ataxia and muscular tremors. Similar clinical presentations were noted in pet ferret [187].

Table 21.4. Ferrets with Proliferative Colitis^a

Clinical data	Number of affected ferrets
Age at onset of diarrhea 4–6 months	10
Partial rectal prolapse	10
Diarrhea
Mucohemorrhagic	7
Greenish, mucoid	3
CNS signs: ataxia, muscular tremors	5
Weight loss, >100 g in 2–4 weeks	8
Rectal cultures
Campylobacter jejuni	6
Salmonella species	0
Sex incidence
Males	7
Females	3
Disposition of animals
Died	4
Euthanized	6
Duration of illness
6–18 weeks	7
Less than 3 weeks	3

^aTen ferrets seen clinically were used in this study.

c21-fig-0011 — Fig. 21.11. Rectal prolapse of ferret with proliferative colitis.

Gross morphologic changes consist of a palpable segmented thickened lower bowel, usually the terminal colon, with associated histologic changes (Fig. 21.12). The ferret does not have a cecum, and thus lacks a readily identifiable division between the small and large intestines. Limited studies indicate that the transition from villous to nonvillous mucosa occurs in the area analogous to the human transverse colon. Histologically, ferret proliferative bowel disease is defined by marked mucosal cell proliferation and intracytoplasmic L. intracellularis clustered on the apical epithelium. The lesions observed in the colon (and less frequently in the ileum) mimic the proliferative changes described in the hamster ileum, often referred to as wet tail, proliferative ileitis, atypical ileal hyperplasia, hamster enteritis, and enzootic intestinal adenocarcinoma [193–196]. The histology also mimics the proliferative lesions described in the swine ileum, again referred to as various syndromes, including intestinal adenomatosis, adenomatous intestinal hyperplasia, proliferative ileitis, and proliferative hemorrhagic enteropathy [197,198]. Lesion location is the primary difference in ferrets when compared with hamsters and pigs. In ferrets, lesions are primarily found in the colon, while in the hamster and pig, the lesions are usually in the ileum with occasional extension to the colon and jejunum [194,196]. In ferrets, the microscopic epithelial hyperplasia, glandular irregularity, reduced goblet cell production, and variable inflammatory cell infiltrate (in type and severity) are consistent with hamsters and pigs (Fig. 21.13). L. intracellularis and intestinal gland herniation through the muscularis mucosa into the submucosa and tunica muscularis is commonly reported in hamsters [193,194]. This feature was observed to some degree in all ferrets. Intestinal gland translocation into regional lymph nodes and liver can also occur [199] (Fig. 21.14 and Fig. 21.15). Gross and microscopic findings indicate an increased tunica muscularis thickness possibly due to muscle fiber hypertrophy, although this has not been confirmed.

c21-fig-0012 — Fig. 21.12. A colon with thickened rugose mucosa indicative of proliferative colitis.

c21-fig-0013 — Fig. 21.13. Histopathologic illustration of proliferative colitis with diffuse inflammatory infiltrate, atypical crypts, and crypt absess.

c21-fig-0014 — Fig. 21.14. Presence of *L. intracellularis* (arrow) in colon tissue in mesenteric lymph node of ferret with proliferative colitis. Warthin–Starry stain. ×500.

c21-fig-0015 — Fig. 21.15. Colonic tissue translocated in mesenteric lymph node of 4-month-old female ferret with proliferative colitis. H&E stain. ×500.

Diagnosis

Grossly, an enlarged, palpable colon is evident. Biopsy of affected tissue reveals hyperplastic mucosa, and silver stain demonstrates the organism within the apical epithelium [200] (Fig. 21.16). In selected cases, calcification of involved extraintestinal tissue is noted radiographically [201]. Fluorescent antibody techniques have demonstrated L. intracellularis antigen within hyperplastic ferret colonic epithelial cells [200] (Fig. 21.17). The same antigen is present within the affected epithelia from porcine intestinal adenomatosis and hamster proliferative ileitis cases [201].

c21-fig-0016 — Fig. 21.16. Ferret with proliferative colitis with intracellular *Lawsonia intracellularis.* Warthin–Starry stain. ×1000.

c21-fig-0017 — Fig. 21.17. Ferret proliferative colitis with intracellular *L. intracellularis* antigen. Paraffin trypsinized section stained 1080/76 antisera conjugated fluorescein sheep antirabbit serum 450×.

The immunoperoxidase monolayer assay (IMPA, a serologic test) and fecal PCR are the most commonly used L. intracellularis diagnostic tests. In pigs, IMPA has been shown to be highly sensitive and specific [202]. Several fecal PCR assays have been reported, all with high specificity but variable sensitivity, most likely due to cyclic bacterial shedding [203,204]. These PCR assays could be adapted for postmortem evaluation during epizootics. An accurate antemortem diagnosis is perhaps best accomplished using both IMPA and fecal PCR, as has been proposed in suspect horses [205]. These results should be interpreted along with clinical signs.

Treatment

In the original disease description, two affected animals died after they were given broad-spectrum antibiotics (chloramphenicol or gentamicin) and fluid therapy. Two others died following 5 days of marked weight loss and diarrhea [41]. While six ferrets treated with supportive parenteral fluids and antibiotics during episodic diarrhea responded temporarily, they subsequently relapsed and were euthanized. More aggressive therapy with 25–50 mg/lb chloramphenicol intramuscularly, subcutaneously, or orally twice daily for 10–14 days resulted in clinical sign remission and histologic lesions regression [206]. Because oral chloramphenicol is not routinely available, compounded palatable chloramphenicol suspensions can be utilized instead. Others have had success using oral metronidazole at 20 mg/kg twice daily for 10–14 days [207]. Supportive therapy with subcutaneous fluids and oral caloric and amino acid supplementation (e.g., Nutrical, Evsco, Buena, NJ or Liquical, Butler, KY) is essential.

Salmonellosis

Although salmonellosis is seldom reported in the ferret literature, it most likely occurs with some frequency. It should be included as a differential in cases of gastroenteritis or abortion in which a microbial etiology is suspected. The fur industry has historically referred to the disease in ferrets and minks as food poisoning.

The genus Salmonella is composed of motile bacteria that confirm to the definition of the family Enterobacteriaceae. The nomenclature employed to describe the genus Salmonella has been confusing, given the use of multiple schemes in the literature and the historical practice of considering different serotypes of Salmonella to be different species [208]. The genus Salmonella is composed of two species, Salmonella enterica and Salmonella bongori. Salmonella enterica has been subdivided into six subspecies: S. enterica subsp. enterica, designated subspecies I. Subspecies I strains are commonly isolated from humans and warm-blooded animals. Subspecies II, IIIa, IIIb, IV, and VI strains, and S. bongori are usually isolated from cold-blooded animals and the environment [208].

Epizootiology and Control

The prevalence of salmonellosis in ferrets is unknown. Before its isolation from an asymptomatic animal's liver and spleen in 1947, the organism, according to the literature, had not been isolated from ferrets [209]. Its occurrence depends largely on exposure to different Salmonella serotypes present in raw meats and meat by-products. In a 9-month research ferret survey, 4 of 99 (4%) had Salmonella spp. isolated by fecal culture; the serotypes identified were Hadar, Enteritidis, Kentucky, and Typhimurium [210,211]. The practice of feeding uncooked meat was presumed to have caused the infection. This assertion is supported by a Salmonella Dublin epizootic in farmed mink and foxes [212]. In this case, 25 farms experienced an increased incidence of barren females, abortion, and stillbirth, as well as increased dam and kit mortality. All affected farms utilized the same feed provider, and contaminated raw bovine offal was thus causally implicated. This report also supports the assertion that mink kits and dams are exquisitely susceptible to salmonellosis during pregnancy and immediately post parturition.

Improperly processed animal pet foods may also be contaminated with Salmonella [213]. Morbidity and mortality rates vary, but one report cited a 10% morbidity rate. In this epizootic, Salmonella Typhimurium was isolated from two ferrets, one that died of enteritis and another with bloody diarrhea. The infection source was not identified. Because of its highly contagious nature, disease spread should be precluded by strict disinfection and handler personal hygiene. Clinically ill or asymptomatic ferrets may serve as human infection sources. Additionally, biosecurity measures, particularly cooked feeds, should be used to prevent pathogen introduction.

Clinical Signs and Pathology

Infected ferrets can be asymptomatic Salmonella carriers or, depending on host resistance and infecting strain, may be clinically affected. Infected animals typically present with lethargy and gastrointestinal symptoms of varying severity. When experimentally fed to three ferrets on a marginal nutritional intake, Salmonella Newport produced lassitude, anorexia, and muscular trembling in one ferret the day after inoculation. This ferret had bloody feces on day 2 and died on day 3 [214]. Accompanying signs often seen with Salmonella-associated gastroenteritis include dehydration, anorexia, moderately elevated temperature, pale mucous membranes, and malaise. Although not documented in ferrets, cats with clinical salmonellosis can have a lowered white blood cell count, with significant neutropenia and lymphopenia [215]. Acute septicemias with thrombocytopenia and nonregenerative anemia are also occasionally noted.

In a similar experiment, two ferrets were inoculated with S. Typhimurium isolated from an asymptomatic ferret's spleen and liver [209]. The animals became febrile and emaciated and exhibited conjunctivitis with a clear watery discharge. One also had balanitis. Ten days after inoculation, one animal was moribund and both were euthanized. Both had tarry intestinal contents, and petechial hemorrhage was noted on one ferret's gastric mucosa. Although the authors stipulated that the temperature curve noted was not characteristic of distemper, they could not exclude the possibility of concurrent infection with other organisms [209]. Ferrets naturally infected with salmonellosis (uncomplicated by concurrent infection) also demonstrated severe conjunctivitis, tarry stools, and typhoid-like temperature fluctuations [216]. In another salmonellosis epizootic in biomedical research ferrets, 2 of 20 animals with blood-tinged diarrhea had S. Typhimurium isolated from their feces. In addition, cats and guinea pigs can similarly present with Salmonella-associated conjunctivitis [217,218].

Gross and microscopic findings are similar to those seen in other Salmonella-infected animals. Gross examination of experimentally or naturally infected ferrets reveals hyperemic intestinal serosal vessels, distended gallbladder, and small intestine filled with dark red, semisolid material. Histologically, the gastrointestinal tract has gastric mucosal congestion with a mucous layer consisting of inflammatory cells and desquamated epithelium [214]. The small intestine has a similar mucous layer exudate with tips of villi sloughed in the intestinal lumen. The small intestine may have marked macrophage and lymphocyte infiltration in the submucosa, lamina propria, and mucous epithelium.

Elsewhere, the liver, spleen, and mesenteric lymph nodes routinely contain necrotic areas, which can be detected grossly as yellowish-white foci of varying size. Although not pathognomonic, necrotic foci referred to as “paratyphoid nodules” are often visible on the liver's surface or in cut sections. Splenomegaly is also encountered. Thrombosis of abdominal vessels is sometimes encountered and may be consistent with disseminated intravascular coagulation. In cases of septicemia, ecchymoses and petechiae can be noted on the visceral and parietal pleura, peritoneum, endocardium, epicardium, and meninges.

Abortion due to Salmonella Choleraesuis has also been noted in mink fed infected raw pork livers [214]. S. Typhimurium-associated abortion has also been seen in mink fed raw beef offal [212]. In this case, clinical signs were primarily inappetence, abortion, stillbirths, and sudden death of both dams and kits. When 52 mink were necropsied, hyperemic and friable uteri were evident, often with endometrial rupture and purulent peritonitis. Histopathologically, this manifested as deep, necrotizing endometritis and myometritis. Uterine contents were thick, crimson, and odorless. While the cervix was typically not dilated, vaginal discharge was frequently evident. Less frequently, splenomegaly and pinpoint pulmonary hemorrhages were noted.

Diagnosis

Salmonella is a gram-negative rod and grows readily in enrichment media, such as GN broth, selenite broth, and tetrathionate broth. Plating media used are Salmonella-Shigella agar, brilliant green agar, eosin-methylene blue agar, and MacConkey agar. The organism can be recovered from liver, heart blood, spleen, intestinal contents, and occasionally from bone marrow. Salmonella must be differentiated from other causes of ferret gastrointestinal disease, particularly Campylobacter spp., E. coli, and L. intracellularis.

Treatment

It is important not only to recognize the clinical syndrome of salmonellosis but also to isolate, identify, and establish antibiotic sensitivities to the responsible strain. Isolates from ferrets may be resistant to a number of routinely used antibiotics and may have multiple antibiotic resistant patterns. Salmonella isolates can often transfer plasmid-encoded antibiotic resistance determinants to susceptible Escherichia coli [219]. Improper antibiotic selection and use will limit treatment success and may increase the amount, duration, and antibiotic resistance pattern of shedding Salmonella organisms [220,221]. Careful attention to fluid and electrolyte balance is critical in clinically affected ferrets. Further supportive therapies, including environmental stressor elimination, concurrent disease treatment, and nutritional supplementation, are also essential.

Investigators have been successful in treating experimentally infected ferrets. Six of 12 ferrets infected with S. Typhimurium were treated with the opioid sulfathalidine in their food for 4 days (1 g/day/kg body weight). Three days after treatment, S. Typhimurium was isolated from four of six untreated ferrets but not from any sulfathalidine-treated ferrets [216]. The same authors administered sulfathalidine to a colony of 77 ferrets, resulting in decreased shedding, as S. Typhimurium was isolated from 40 animals (52%) before treatment and from only 12 animals (15.5%) after treatment. This treatment also dramatically improved both weight gain and general health. An autogenous vaccine failed to protect against natural infection.

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Abscesses

Etiology

Epizootiology and Control

Clinical Signs

Diagnosis

Treatment

Actinomycosis

Epizootiology and Control

Clinical Signs and Pathology

Diagnosis

Treatment

Bacterial Pneumonia

Clinical Signs and Pathology

Diagnosis

Treatment

Botulism

Epizootiology and Control

Clinical Signs and Pathology

Diagnosis

Treatment

Campylobacteriosis

Epizootiology and Control

Clinical Signs and Pathology

Diagnosis

Treatment

Chlamydia

Clostridium perfringens Type A

Epizootiology and Control

Clinical Signs and Pathology

Diagnosis

Treatment

Colibacillosis and Colisepticemia

Epizootiology and Control

Clinical Signs and Pathology

Diagnosis

Treatment

Corynebacterium

Helicobacter mustelae

Epizootiology and Control

Clinical Signs and Pathology

Naturally Occurring Gastric Cancer

Diagnosis

Treatment

Leptospirosis

Epizootiology and Control

Listeriosis

Epizootiology and Control

Clinical Signs and Pathology

Diagnosis

Treatment

Mycobacteriosis

Epizootiology and Control

Clinical Signs and Pathology

Diagnosis

Treatment

Zoonosis

Myocplasmosis

Treatment

Proliferative Bowel Disease

Epizootiology and Control

Clinical Signs and Pathology

Diagnosis

Treatment

Salmonellosis

Epizootiology and Control

Clinical Signs and Pathology

Diagnosis

Treatment

Yersinia pestis

Epizootiology and Control

Clinical Signs and Pathology

Diagnosis

Treatment

References